Genetic Variant FUCA1:p.Ala3Pro (chr1-23868280-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000147.5(FUCA1):c.7G>C(p.Ala3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00963 in 1,549,772 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0094 ( 21 hom., cov: 32)

Exomes 𝑓: 0.0096 ( 119 hom. )

Consequence

FUCA1
NM_000147.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.15

Publications

4 publications found

Variant links:

Genes affected

FUCA1 (HGNC:4006): (alpha-L-fucosidase 1) The protein encoded by this gene is a lysosomal enzyme involved in the degradation of fucose-containing glycoproteins and glycolipids. Mutations in this gene are associated with fucosidosis (FUCA1D), which is an autosomal recessive lysosomal storage disease. A pseudogene of this locus is present on chr 2.[provided by RefSeq, Oct 2009]

FUCA1 Gene-Disease associations (from GenCC):

fucosidosis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen, Orphanet, Genomics England PanelApp

FUCA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022031665).

BP6

Variant 1-23868280-C-G is Benign according to our data. Variant chr1-23868280-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 296895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00942 (1435/152270) while in subpopulation AMR AF = 0.0422 (646/15300). AF 95% confidence interval is 0.0395. There are 21 homozygotes in GnomAd4. There are 747 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000147.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FUCA1	NM_000147.5	MANE Select	c.7G>C	p.Ala3Pro	missense	Exon 1 of 8	NP_000138.2	P04066
FUCA1	NR_174379.1		n.11G>C		non_coding_transcript_exon	Exon 1 of 8
FUCA1	NR_174380.1		n.11G>C		non_coding_transcript_exon	Exon 1 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FUCA1	ENST00000374479.4	TSL:1 MANE Select	c.7G>C	p.Ala3Pro	missense	Exon 1 of 8	ENSP00000363603.3	P04066
FUCA1	ENST00000965619.1		c.7G>C	p.Ala3Pro	missense	Exon 1 of 8	ENSP00000635678.1
FUCA1	ENST00000881205.1		c.7G>C	p.Ala3Pro	missense	Exon 1 of 7	ENSP00000551264.1

Frequencies

GnomAD3 genomes

AF:

0.00942

AC:

1434

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00227

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0423

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0159

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00841

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.0153

AC:

2170

AN:

142052

AF XY:

0.0144

show subpopulations

Gnomad AFR exome

AF:

0.00247

Gnomad AMR exome

AF:

0.0506

Gnomad ASJ exome

AF:

0.00147

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00146

Gnomad NFE exome

AF:

0.00797

Gnomad OTH exome

AF:

0.0134

GnomAD4 exome

AF:

0.00965

AC:

13485

AN:

1397502

Hom.:

119

Cov.:

AF XY:

0.00971

AC XY:

6702

AN XY:

690158

show subpopulations

African (AFR)

AF:

0.00185

AC:

AN:

31856

American (AMR)

AF:

0.0518

AC:

1886

AN:

36438

Ashkenazi Jewish (ASJ)

AF:

0.00127

AC:

AN:

25206

East Asian (EAS)

AF:

0.000138

AC:

AN:

36260

South Asian (SAS)

AF:

0.0157

AC:

1252

AN:

79972

European-Finnish (FIN)

AF:

0.00155

AC:

AN:

42698

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

4834

European-Non Finnish (NFE)

AF:

0.00883

AC:

9559

AN:

1082230

Other (OTH)

AF:

0.00991

AC:

575

AN:

58008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

711

1422

2132

2843

3554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

398

796

1194

1592

1990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00942

AC:

1435

AN:

152270

Hom.:

Cov.:

AF XY:

0.0100

AC XY:

747

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00226

AC:

AN:

41572

American (AMR)

AF:

0.0422

AC:

646

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.0164

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00840

AC:

571

AN:

68010

Other (OTH)

AF:

0.0118

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

153

230

306

383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00383

Hom.:

Bravo

AF:

0.0118

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00119

AC:

ESP6500EA

AF:

0.00254

AC:

ExAC

AF:

0.00669

AC:

703

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Fucosidosis (2)

FUCA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.58

CADD

Benign

1.5

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.072

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.25

MetaRNN

Benign

0.0022

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

PhyloP100

-2.2

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.34

REVEL

Benign

0.067

Sift

Benign

0.17

Sift4G

Benign

0.084

Polyphen

0.0

Vest4

0.17

MPC

0.47

ClinPred

0.020

GERP RS

-3.6

PromoterAI

0.37

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.086

gMVP

0.52

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over